AHEART July 46/1

Shigematsu, Sakuji, Shuji Ishida, Dean C. Gute, and Ronald J. Korthuis. Concentration-dependent effects of bradykinin on leukocyte recruitment and venular hemodynamics in rat mesentery. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H152–H160, 1999.—The results of several recent studies indicate that bradykinin protects tissues against the deleterious effects of ischemia-reperfusion (I/R). However, other studies indicate that bradykinin can act as a proinflammatory agent, inducing P-selectin expression, the formation of chemotactic stimuli, and endothelial barrier disruption. In the present study, we used intravital microscopic techniques to examine the dose-dependent effects of bradykinin on leukocyte-endothelial cell interactions, the formation of platelet-leukocyte aggregates, and venular hemodynamics in rat mesentery in an attempt to explain these divergent findings. Superfusion of the mesentery with low concentrations of bradykinin (#1027 M) increased venular erythrocyte velocity (VRBC) without increasing the number of adherent leukocytes, whereas higher concentrations ($1026 M) decreased VRBC, increased the number of platelet-leukocyte aggregates, and induced leukocyte adhesion in single postcapillary venules. The formation of platelet-leukocyte aggregates and increased leukocyte adhesion induced by high-dose bradykinin were attenuated by administration of a B2-receptor (HOE-140) or a platelet-activating factor (PAF, WEB-2086) antagonist. Thus these adhesive interactions induced by high-dose bradykinin appear to be mediated by a mechanism that is dependent on B2-receptor activation and the formation of PAF or PAF-like lipids. The effects of bradykinin on venular VRBC and blood flow were also concentration dependent, with low doses producing nitric oxide-mediated vasodilation, whereas high doses decreased VRBC by a mechanism that is PAF independent.